In the ARROW study, Gainor et al attempted to evaluate the safety, tolerability, and antitumor activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion–positive non–small cell lung cancer (NSCLC). The study enrolled patients aged 18 years or older with locally advanced or metastatic solid tumors, including RET fusion–positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0 to 2 (later limited to 0-1 in a protocol amendment). In phase II, patients received 400 mg once-daily oral pralsetinib and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. The phase II primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumors version 1.1 and evaluated by blinded independent central review) and safety.

In this study, the researchers found that of the 233 patients with RET fusion–positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrollment cutoff); 87 previously treated patients; and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Among the 87 previously treated patients, objective response was noted in 53 (61%, 95% confidence interval [CI] = 50%-71%), including complete response in five (6%). Responses were noted irrespective of RET fusion partner, previous multikinase inhibitor treatment, and previous PD-1 (programmed cell death protein) or PD-L1 (programmed death-ligand 1) inhibitor treatment. At an average follow-up from first response of 12.9 months, average duration of response was not achieved (95% CI = 15.2 months–not estimable), with 83% of responses maintained at 6 months and 74% maintained at 12 months.

The average progression-free survival was 17.1 months at an average follow-up of 14.7 months, and the median overall survival was not achieved at a median follow-up of 17.1 months. Among the 27 treatment-naive patients, objective response was noticed in 19 (70%, 95% CI = 50%-86%), with complete response in 3 (11%). Responses were observed irrespective of RET fusion partner, and average duration of response was 9 months (95% CI = 6.3 months–not estimable) at an average follow-up of 10.2 months. Average progression-free survival was 9.1 months at an average follow-up of 11.6 months. Moreover, average overall survival was not reached at a median follow-up of 13.6 months.

Among all 233 patients with RET fusion–positive NSCLC who received pralsetinib in the study, treatment-related grade ≥3 adverse events appeared in 48%, with the most common adverse events reported as neutropenia (18%), hypertension (11%), and anemia (10%). An estimated 24% reported serious treatment-related adverse events, with the most common being pneumonia (4%), pneumonitis (4%), anemia (2%), and neutropenia (2%). Treatment-related adverse events led to termination of treatment in 6% and adverse events led to death in 6% of patients, with none considered related to treatment. The researchers concluded that pralsetinib is a novel, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion–positive NSCLC.

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